Testing the Ability of JNJ-18038683 to Improve Cognition and Reduce Depressive Symptoms in Stable Bipolar Patients

Brief description of study

The goals of this study are to evaluate the efficacy of JNJ-18038683 in an 8 week trial to
ameliorate the cognitive deficit and reduce residual depressive symptoms in 60 stable bipolar
outpatients receiving treatment for depression. JNJ-18038683 will be studied and compared
with placebo as adjunctive treatment to standard pharmacologic treatment for bipolar
disorder.

Detailed Study Description

Most, but not all, patients with bipolar disorder (BPD) have clinically significant cognitive
impairment. Impairment is present in both the manic and depressed phases of BPD, as well as
in euthymic periods. The percentage of BPD patients with cognitive impairment (CIBD) varies
among studies, with 40-60% representing the best estimate. The weight of the evidence
supports no overall difference in the type and severity of cognitive impairment in any phase
of BPD, i.e. it is a stable trait feature of BPD, albeit variable from one patient to
another. The most commonly affected cognitive domains are speed of processing, declarative
memory, attention and working memory. Although CIBD is milder in severity than the cognitive
impairment associated with schizophrenia (CIAS), on average, as in schizophrenia, CIBD has a
major impact on function and quality of life in most patients, particularly because the
greater preservation of function of BPD enables them to engage in activities which are more
dependent on intact cognitive function. Thus, it is highly likely that improvement in CIBD
will have valuable clinical benefit, especially with regard to quality of life measures. It
is reasonable to predict that treatments effective to improve CIBD could also be beneficial
for CIAS. Efficacy for cognitive impairment is likely to be greater in BPD than
schizophrenia, because the baseline severity is milder in the former. Despite this strong
rationale for targeting CIBD, there has been minimal focus on clinical trials to improve
CIBD, perhaps because so many resources have been devoted to the effort to treat CIAS, but
lack of appreciation of the severity of CIBD and its importance as a determinant of
functional outcome in BPD may be the most important factors.

In a recent study of CIBD, using the MATRICS Consensus Cognitive Battery (MCCB), impairment
was found in both treatment resistant BP I and II depressed inpatients within all MCCB
domains. The greatest impairment was evident in speed of processing, declarative memory and
attention. The impairment was numerically greater in BP I than BP II patients but the
difference was not significant. Compared to normal controls, the deficits, in BP 1 patients,
in speed of processing was 1.2SD, in attention, 1.0 SD, and in verbal learning, 1.8 SD. The
least affected domain was visual learning, with a mean deficit of 0.8SD compared to normal
controls. The mean composite score deficit was 1.25 SD. Medication for BPD, particularly mood
stabilizers, may adversely affect some domains of cognition in BPD. However, antidepressant
medications have not been found to affect the severity of cognitive impairment in major
depression or BPD.

Based on the pre-clinical, pro-cognitive effects of 5-HT7 antagonism in our laboratory, along
with the reported pre-clinical antidepressant effects of JNJ-18038683, we propose to conduct
a randomized, placebo- controlled parallel, design study to assess the effects of
JNJ-18038683 on multiple domains of cognition and mood symptoms. Since our preclinical
studies show that 5-HT7 receptor blockade is highly effective in improving declarative memory
in rodents, the declarative memory measures will be the primary outcome measures.

Due to the effect of JNJ-18038683 on depressive symptoms in preclinical paradigms, we will
investigate the following in the clinical trial the potential antidepressant effect of
JNJ-18038683 on patients with baseline MADRS score between 8 and 20.